Primary cutaneous T-cell lymphomas (CTCL) represent a heterogeneous group of non-Hodgkin-lymphomas (NHL) whose etiology and pathomechanism are poorly understood [Siegel, R. S., et al., J. Clin. Oncol. 18 (2000) 2908-2925]. There is no curative therapy for CTCL. During the last ten years an increase of about 2-8% in the incidence of CTCL has been observed in the developed world [Doll, R., et al (Eds.), Trends in cancer incidence and mortality, cancer surveys, Vol 19/20, Cold Spring Harbor Laboratory Press, 1994, 423-53; Hjalgrim, H., et al., Br. J. Cancer 73 (1996) 951-54]. After the group of primary gastrointestinal lymphomas, CTCL together with the primary cutaneous B-cell lymphomas form the second most common group of extra-nodal NHL [Isaacson, P. G. and Norton, A. J., Cutaneous lymphoma, in Extra-nodal lymphomas, London, Churchill Livingstone, 1994, p. 172]. In Finland, a three-fold increase in the incidence of CTCL has been found in men, but not in women, during the last 40 years [Väkevä, L., et al., J. Invest. Dermatol. 115 (2000) 62-65].
A major portion, about 80%, of the CTCL patients usually show an indolent disease course and long remissions may be achieved with treatment. However, about 20% of the cases undergo a transformation into an aggressive large-cell variant so that the tumour cells invade several tissues, such as skin, blood, lymph nodes, and bone marrow, and there is some evidence that this is the original malignant cell clone [Wolfe, J., et al., J. Clin. Oncol. 13 (1995) 1751-57]. The 5-year survival of these patients is below 15% [Willemze, R., et al., Blood 90 (1997) 354-371; Siegel, R. S., et al., supra]. This transformation cannot be predicted by any current means.
The most common form of CTCL is mycosis fungoides (MF). The first skin lesions develop slowly. They resemble eczema or mild psoriasis and are called Parapsoriasis en plaques (Pps). In the early phases, poly- or oligoclonal CD4-positive lymphocytes infiltrate towards the epidermis of the skin. The time and the compartment of the malignant transformation are not known [Veelken, H., et al., J. Invest. Dermatol. 104 (1995) 889]. Malignant lymphocytes are later found also in blood and lymph nodes. However, recent data suggest that the malignant cells may be dispersed even earlier than previously thought [Karenko, L., et al., J. Invest. Dermatol. 108 (1997) 22-29; Karenko, L., et al., J. Invest. Dermatol. 112 (1999) 329-95: Karenko L, et al., J. Invest. Dermatol. 16 (2001) 188-193].
A more aggressive form of CTCL is the leukaemic Sezary syndrome (SS), which may evolve from MF or begin directly with erythrodermic skin symptoms.
In the treatment of CTCL, an early diagnosis is crucial, because the disease is prone to relapse in later stages. However, no means are available at present for a definite diagnosis of CTCL. In particular, MF is difficult to diagnose in its early presentations due to its resemblance to eczema or mild psoriasis and unfortunately may thus remain undetected in time. In the diagnosis of CTCL, a skin biopsy sample is obtained from the affected skin area and a histopathological analysis is performed. The histopathological diagnosis is based on the detection of epidermotropic, morphologically malignant lymphocytes, i.e. cells with hyperchromatic, indented (cerebrifom) nuclei (Willemze, R., et al., supra). In most, but not all, cases these cells express the CD4 surface marker, which may be detected immunohistochemically (Willemze, R., et al., supra). Thus, the diagnostic accuracy depends on visual grading and impression made by a pathologist, and early lesions with only very few malignant cells or with chromosomally clonal malignant lymphocytes with as yet normal morphology may be missed.
Additionally, the demonstration of T-cell receptor (TCR) rearrangement in blood or skin lesion-derived DNA has been used as a supplementary method in the diagnosis of CTCL. However, TCR rearrangement is not a disease-specific marker, since it identifies also reactive clonal cells [Guitart J. and Kaul K., Arch. Dermatol. 135 (1999) 158-62].
Also several chromosomal aberrations, especially numerical aberrations, have been observed in CTCL in molecular cytogenetic studies and these can be used in the diagnosis. In particular, the cytogenetic changes have been shown to precede the histologically identifiable malignancy [Whang-Peng, J., et al., Cancer 50 (1982) 1539; Berger, R., et al., Cancer Genet Cytogenet 27 (1987) 79; Karenko et al., 1997, supra]. However, in the early phases of the disease these abnormalities have been non-clonal, which renders the detection non-specific.
It is of highest importance to develop new methods, which enable an early diagnosis and the follow-up of therapeutic interventions in terms of residual malignant cells in lymphoproliferative diseases, such as CTCL. Also, additional means for the development of new guidelines for the initiation and follow-up of therapy are greatly needed.